Perspective on Pharm/Tox Assessment for Cell and Gene Therapy Products

1. Perspective on Pharm/Tox Assessment for Cell and Gene Therapy Products Ying Huang, Ph.D. Pharmacologist Center for Biologics Evaluation and Research FDA

2. Presentation Outline • Regulatory expectations • OCTGT regulated CT and GT products • Preclinical evaluation • Potential safety concerns for CT and GT products • Pharm/Tox study designs • The use of animal species/models • Preclinical data in the IND • Communication with the FDA

3. Safety is Always Primary • FDA Regulatory & Scientific Input • ICH documents • FDA guidance/PTCs/21 CFR Clinical Trials IND Submission For Early Phase Clinical Trial Biologics License Application (BLA) • Basic Research • POC Studies • Biodistribution • Toxicology Product License Granted • PreIND discussion with FDA Discovery Phase / Safety Assessment

4. How Are Animal Studies Integrated into the Proposed Clinical Plan? • 21 CFR, part 312.23(a)(8) Pharmacologic & Toxicologic Studies • “…adequate information about the pharmacological & toxicological studies…on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations. The kind, duration, & scope of animal and other tests required varies with the duration & nature of the proposed clinical investigations.”

5. CT and GT IND/IDE Submissions in CBER CT = cell therapy, GT = gene therapy, XP = xenotransplantation

6. OCTGT-Regulated Products • Somatic cell therapies • Gene Therapies • Viral therapies, e.g. oncolytic viruses • Immunotherapies, e.g. tumor vaccines • Xenotransplantation • Tissue engineering* • OCTGT Product + device* * in conjunction with CDRH

7. Product Examples • Cell Therapy Products • Progenitor cells, e.g. stem cells derived from various types of human tissues, embryos, and hematopoietic stem cells… • Differentiated cells, e.g. islet cells, cartilage cells, dendritic cells, T lymphocytes… • Gene Therapy Products • Many types of replication deficient viral vectors • Plasmid DNA vectors • Various types of transgenes delivered by those vectors

8. Product Examples (cont.) • Oncolytic Vectors • Replication competent or attenuated viruses for the treatment of various type of cancers via viral lysis of tumor cells • Therapeutic Vaccines • Tumor vaccines for cancer immunotherapy • Vaccines for the treatment of nononcology diseases such as Alzheimer’s disease

9. Types of Vectors for GT • Plasmid DNA: • Naked DNA • Lipid-DNA complex • Ligand-DNA complex • Others, e.g. bacteria-based gene transfer

10. Types of Vectors for GT (cont.) • Replication Deficient Viral Vectors • Retroviruses • Adenoviruses • Adeno-associated viruses • Vaccinia/fowlpox viruses • Herpes simplex viruses • Lentivirus • Other newer vectors on the horizon ….

11. Routes of Gene Transfer • Ex vivo (transduction of cells in vitro) • Transduced somatic cells • Transduced hematopoietic cells • In situ (local delivery) • Direct administration into specific tissues (e.g. intratumoral injection, s/c injection, etc.) • In vivo (systemic delivery) • Intravenous administration, etc…

12. Regulatory expectations • OCTGT regulated CT and GT products • Preclinical evaluation • Potential safety concerns for CT and GT products • Pharm/Tox study designs • The use of animal species/models • Preclinical data in the IND • Communication with the FDA

13. Preclinical Expectations for Early Phase Clinical Trials • Scientific basis for conducting clinical trial • Feasibility/establishment of rationale • “Proof-of-concept” [POC] • Establish pharmacologically effective dose(s) • Optimize ROA/dosing regimen • Rationale for species/model selection for further tests

14. Preclinical Expectations (cont.) • Recommend initial safe dose & dose escalation scheme in humans • Potential target tissue(s) of toxicity/activity • Parameters to monitor clinically • Eligible patient population

15. Preclinical Evaluation – CT/GT Agents vs. “Traditional” Biologics • Similar general requirements for safety • Pharmacologic profiles • Proof-of-Concept (POC) • Dose-response relationship • Toxicology profile

16. Preclinical Evaluation – CT & GT Agents • BUT… the approach by which safety data are obtained will differ Gene Therapy…………Cell Therapy • Migration potential • Differentiation • Phenotype expressed • Anatomical/functional integration into host physiology • Post-transplant survival • Biodistribution of vector • Kinetics of gene expression

17. Preclinical Evaluation – CT & GT Agents (cont.) Gene Therapy.…………...Cell Therapy Long-term toxicity • Tumorigenicity/ • proliferative potential: • Carcinogenicity/ insertional mutagenesis: • Depends on the product • Consider the ROA • Include appropriate study duration

18. Preclinical Evaluation – CT & GT Agents (cont.) Gene Therapy.…………… Cell Therapy Long-term toxicity • Reproductive Toxicity • Consider a tiered approach • Based on the BD data of the vector • Determine the need to address the risk of germline transfer, then • Determine the need to conduct reproductive and developmental toxicology studies • ICH S5(R2) guideline should be consulted for the overall design of these studies

19. Potential Safety Concerns for CT Products • Risk analysis based on CT products • Cell survival status following delivery • Cell migration/trafficking to non-target site(s) • Cell differentiation to undesired cell types • Immunogenicity to xenogeneic/allogeneic cells • Uncontrolled cell proliferation or tumorigenicity • Host response (physiologic, anatomic, the use of immunosuppressants, etc.)

20. Potential Safety Concerns for GT Products • Risk analysis based on GT products: • Phenotype/activation state of target cell(s) • Type of vector, mode of introduction • Vector biodistribution to non-target cells • Level and/or persistence of vector genome • Level of viral replication in non-target tissues • Inappropriate immune activation • Potential for insertional mutagenesis and/or oncogenicity

21. Potential Safety Concerns forGT Products (cont.) • Transgene related concerns • Expression of endogenous or recombinant enzymes, receptors, ligands, hormones, growth factors, oligonucleotides (anti-sense, siRNA, etc…) • Local vs. systemic activities • Acute or chronic effects • Immunogenicity • Autoimmunity

22. Pharm/Tox Studies • Pharmacology/POC studies • Relevance of animal species/models • Dose levels/regimen at which the desired biological activity can be observed via the proposed ROA • Toxicology (T) studies in a healthy animal that is biologically relevant for safety assessment • Hybrid pharmacology-toxicology study design • POC + T – Obtain toxicology endpoints in an animal model of disease

23. Toxicology Study Design • Appropriate controls • Mimic clinical scenario as closely as possible • Product, formulation, ROA, dose regimen, etc. • Reasonable group size to provide adequate interpretation of the data • The number of animals will vary depending on the species, disease model, delivery system, product class, etc.

24. Toxicology Study Design (cont.) • Sufficient duration, depending on the biology of the test product, to allow for appearance of any toxicities…and the potential for resolution of toxicities • Use several time points to evaluate early, middle and late findings following dosing • Include the time point at which the toxicities are expected to be reversed/resolved

25. Toxicology Study Design (cont.) • Selection of dose levels • Include multiple dose levels in order to determine No-Observed-Adverse-Effect-Level (NOAEL) • NOAEL will help to determine a safe starting dose level and dose escalation scheme in the clinical trial • Need repeat dose toxicology study to support safety of a repeat dosing regimen in the clinical trial

26. Toxicology Study Design (cont.) • Standard Toxicology Endpoints • Mortality • Clinical observations, body weights, appetite • Hematology and coagulation • Serum chemistry • Immune effects (humoral or cellular immune responses) • Gross pathology (scheduled and unscheduled deaths) • Microscopic pathology • Scheduled and unscheduled deaths • Examine both target and non-target tissues • Specific immunohistochemistry staining

27. Pharm/Tox Study Design for CT Products • The guiding principles for POC and safety studies remain the same for CT and GT products • Specific safety endpoints include cell survival, undesired cell differentiation and proliferation, immunogenicity to xenogeneic/allogeneic cells, host tissue/organ response… • Safety endpoints may vary • Depending on the product • Considering the ROA • Appropriate study duration may also vary

28. Pharm/Tox Study Design forCT Products (cont.) • ‘Hybrid’ studies may be conducted to provide rationale and safety data • Cell trafficking data may be needed depending on the product and ROA • The advisory committee recommendations (e.g. BRMAC* for cardiac CT) are also an important source of information for guiding safety assessment *Now called CTGTAC

29. Vector Biodistribution (BD) Studiesfor GT Products • Use of a relevant species, e.g. the same species as used in the toxicology study • Usually the maximum feasible dose and/or NOAEL dose levels used in toxicology study • Administered via the clinical ROA, i.e. used in toxicology study • Biodistribution profile in both target and non-target tissues, including the blood • Guidance for Industry: Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events

30. Vector BD Studies for GT Products – Specific Considerations • Novel GT products: the BD data need to be completed prior to initiation of clinical trials to assess vector persistence & kinetic profile • GT products similar to those previously used in humans: • Safety database in humans • BD data in animals by cross-reference to other INDs • Conduct of BD study in parallel with early phase clinical trials • BD data using the clinical material are needed for license application and labeling

31. CT & GT Dose Extrapolation • The objective is to recommend a startingclinical dose level and doseescalation schemethat are safe and biologically plausible • Dose extrapolation between animals and humans based on: • POC data – minimally active dose level • Safety data from animal studies (e.g. toxicology, vector BD, cell migration) - NOAEL • Calculation of clinical dose levels based on • Fixed dose level (e.g., absolute dose) • Body weight • Organ mass (volume/weight)

32. Preclinical Safety Evaluation – Other Issues – Devices • Is this device approved/cleared for the intended use? • If not - has an IDE/MF been submitted to CDRH? • Yes - Need to include a letter of cross reference in your IND • No - Need to consult with CDRH as to what data are required for submission • Perform preclinical safety evaluation studies using the intended clinical device, if possible

33. Selection of Appropriate Animal Species • The use of NHPs is not required • The use of multiple species (e.g. a rodent and a non-rodent) is not required …..BUT….. Scientific justification must be provided for the selection of the animal species/model

34. Selection of Animal Species/Model • Use of relevant species/model • Traditional • Normal animals; rodent & non-rodent • Non-traditional • Spontaneous disease • “Non-spontaneous” disease (induced, challenge) • Genetically modified animals (e.g. “humanized” or transgenic animals)

35. Selection of Animal Species/Model (cont.) • Use of large animal models may be needed for preclinical assessment of CT/GT products • Depends on the product • Depends on the ROA • Depends on the delivery system

36. Preclinical Summary • Pharm/Tox studies for CT & GT should be: • Rational, problem-solving in study design • Assessments based on the best available technology, methods to date • Conclusions are data-driven • Scientifically designed & judicious use of animals • Should allow for early initiation of clinical trials • Should allow uninterrupted clinical development

37. Preclinical Summary (cont.) • Some limitations of preclinical studies for CT and GT products • Information on mechanism of action is often limited • Biologically relevant animal species or model(s) of disease are not always available • Limited information is available to support the validity of extrapolation from animal to human • No one species will be representative or predictive for all humans, including humans

38. Regulatory expectations • OCTGT regulated CT and GT products • Preclinical evaluation • Potential safety concerns for CT and GT products • Pharm/Tox study designs • The use of animal species/models • Pharm/Tox data in the IND • Communication with the FDA

39. Sources of Preclinical Pharmacology Data • Pharmacology data in support of a clinical trial can come from: • Well-controlled studies conducted in-house • Published data in peer-reviewed journals • Cross-reference to similar products in previously submitted MF/INDs

40. Sources of Toxicology Data • Toxicology data in support of a clinical trial can come from: • GLP-compliant toxicology studies • Well-controlled studies conducted in-house • Published data in peer-reviewed journals • Cross-reference to similar products in previously submitted MF/INDs

41. Perils of Using Published Animal or Human Studies as Sole Support for Initiation of Clinical Trials • Often they were not designed to answer a toxicologic question, and therefore, adequate toxicology endpoints may not have been incorporated into the design • Published reports often do not provide sufficient information for independent review • Products were not comparable/substantially similar

42. Submit Complete Study Reports • Not just summarized statements • Detailed description of the study performed • Test system (i.e. animal species/model) • Test articles/ROA/delivery system • Study methodology - dose levels; dose schedule; dose procedure; test parameters, etc… • Complete data sets for all parameters evaluated • Submit individual animal data for all parameters evaluated • Submit summarized and tabulated results

43. Regulatory expectations • OCTGT regulated CT and GT products • Preclinical evaluation • Potential safety concerns for CT and GT products • Pharm/Tox study designs • The use of animal species/models • Pharm/Tox data in the IND • Communication with the FDA

44. Early Communication • Pre-preIND interactions • Non-binding, informal scientific discussions between Pharm/Tox in OCTGT/CBER and sponsor • Pre-IND meetings • Submit a pre-IND package to include: • Product development/characterization – Chemistry, Manufacturing and Controls (CMC) • Summary of preclinical information – Pharmacology, Toxicology study protocol/plan • Proposed clinical protocol outline • Schedule a pre-IND teleconference

45. Selected Guidance Documents • Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological products www.fda.gov/cder/guidance/1397fnl.pdf • Guidance for Industry: Guidance for Human Somatice Cell Therapy and Gene Therapy (1998) www.fda.gov/cber/gdlns/somgene.pdf • The ICH S6 document: Preclinical Safety Evaluation of Biotechnology Derived Pharmaceuticals www.fda.gov/cder/guidance/1859fnl.pdf • Guidance for Industry: Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events www.fda.gov/cber/gdlns/gtclin.pdf

46. The Pharm/Tox Branch (PTB) at OCTGT/DCEPT • Mercedes Serabian, M.S. DABT, Branch Chief; Initial contact for pre-preIND interactions • A total of 7 reviewers including the BC: Interdisciplinary scientists - biologist, chemist, pharmacologist, toxicologist, and ORISE Fellow (301) 827-5102 [phone]; (301) 827-9796 [fax]

47. CME Questions • For the development of a replication-deficient adenoviral vector expressing the extracellular domain of the HER2 gene as a tumor vaccine for immunotherapy to treat cancer patients, • What preclinical studies or endpoints might be useful in supporting the clinical proof of concept? • What types of preclinical studies are needed to support safety of the proposed clinical trial? • Please propose your scheme for scaling from animal to human safe doses.